Allergic and inflammatory disorders such as allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), allergic conjunctivitis, and atopic dermatitis affect roughly one-fifth of the world population. Symptoms arising from antigenic challenge, including bronchoconstriction, bronchial hyperactivity, sneezing, nasal discharge, and nasal congestion, have been shown to correspond with the release of multiple mediators from inflammatory cells. Current therapies that effectively treat some of these symptoms have arisen out of compound classes including antihistamines, leukotriene antagonists, and corticosteroids. Many existing medicines suffer from side effects such as headache, sleepiness, sedation, dyspepsia, hydrodipsia, pharyngitis, and oral candidiasis. In addition, many of these individual therapies, although treating some symptoms, may fail to address a broader range of symptoms that affect patient quality of life. Antihistamines, for example, treat some of the most unpleasant symptoms of allergy, but have little therapeutic benefit against nasal congestion.
Immunological challenge results in the release of prostaglandin D2 (PGD2), the primary allergic and inflammatory mediator, from inflammatory cells. PGD2, a metabolite of arachidonic acid, activates both the DP1 (DP) and DP2 (CRTH2) receptors, which play a central role in airway inflammation (Spik, I., Brenuchon, C., Angeli, V., et al. J. Immunol., 174, 2005, 3703-3708; Urade, Y., Hayaishi, O. Vitamin and Hormones, 58, 2000, 89-120).
Prostaglandin D synthase (PGDS) catalyzes the conversion of the common prostanoid precursor prostaglandin H2 (PGH2) to PGD2. Two distinct forms of PGDS, lipocalin PGDS (L-PGDS) and hematopoietic PGDS (H-PGDS) have been identified and characterized (Kapoor, M., Kojima, F., Yang, L., and Crofford, L. J. Prostaglandins Leukot. Essent. Fatty Acids, 76(2), 2007, 103-112; Herlong, J. L., Scott, T. R. Immunology Letters, 102, 2006, 121-131; Urade, Y., Fujimoto, N., and Hayaishi, O. J. Biol. Chem., 260, 1985, 12410-12415; Kanaoka, Y., Ago, H., Inagaki, E., et al. Cell, 90, 1997, 1085-1095).

L-PGDS is a glutathione-independent 26 kDa secretory protein that is regarded as the major generator of PGD2 in the central nervous system. L-PGDS is involved in the regulation of sleep (Pinzar, E., Kanaoka, Y., Inui, T., Eguchi, N., Urade, Y., and Hayaishi, O. Proc. Natl. Acad. Sci. U.S.A., 97, 2000, 4903-4907) and pain (Eguchi, N., Minami, T., Shirafuji, N., et al. Proc. Natl. Acad. Sci. U.S.A., 96, 1999, 726-730).
H-PGDS is a 26 kDa cytosolic protein that catalyzes the conversion of PGH2 to PGD2 in a glutathione-dependent manner. This sigma class glutathione S-transferase (GST) is localized in mast cells, antigen-presenting cells, and Th2 cells, and is involved in allergic and inflammatory response (Urade, Y., Mohri, I., Aritake, K., Inoue, T., Miyano, M. Functional and Structural Biology on the Lipo-network, 2006, 135-164; Kanaoka, Y., Urade, Y. Prostaglandins Leukot. Essent. Fatty Acids, 69, 2003, 163-167).
H-PGDS inhibition provides a novel method for preventing and/or treating allergic and respiratory diseases or conditions through the suppression of PGD2 synthesis. Most current therapies function subsequent to mast cell activation and/or degranulation and the formation and release of PGD2. H-PGDS inhibitors, however, have been found to block the formation of PGD2 in vitro (Ikai, K., Ujihara, M., Fujii, K., Urade, Y. Biochemical Pharmacology, 38(16), 1989, 2673-2676). In addition, the weak H-PGDS inhibitor HQL-79 has shown antiallergic and antiasthmatic activity in vivo (Matsushita, N., Hizue, M., Aritake, K., et al. Jpn. J. Pharmacol., 78, 1998, 1-10; Matsushita, N., Aritake, K., Takada, A., et al. Jpn. J. Pharmacol., 78, 1998, 11-22). Other PGDS inhibitors have been reported (US Patent Application No. US 2008/0146569 A1; PCT International Application No. WO 2007/041634 A1; PCT International Application No. WO 2005/094805 A1; PCT International Application No. WO 2007/007778).
Evidence suggests that the modulation of H-PGDS activity should be of therapeutic benefit in indications related to elevated PGD2 levels. These indications include, but are not limited to, allergic rhinitis, perennial rhinitis, rhinorrhea, nasal congestion, nasal inflammation, all types of asthma, COPD, allergic conjunctivitis, arthritis, atopic dermatitis and other types of dermal inflammation, ocular inflammation, wound healing, dermal scarring, and muscular necrosis (i.e. Duchenne muscular dystrophy; American Journal of Pathology, 174(5), 2009, 1735-1744). Efficacious doses of H-PGDS inhibitors may provide both therapeutic benefits and improved safety profiles over existing therapies used for these indications. Recent evidence also suggests that PGD2 produced by H-PGDS plays a role in fever induction (Journal of Physiology and Pharmacology, 60(2), 2009, 145-150).
Compounds have now been found that are inhibitors of H-PGDS, and at expected efficacious doses, do not significantly inhibit L-PGDS.